Prostacyclin Synthase Deficiency Leads to Exacerbation or Occurrence of Endothelium-Dependent Contraction and Causes Cardiovascular Disorders Mainly via the Non-TxA2 Prostanoids/TP Axis.

BACKGROUND: Prostaglandin I2 synthesized by endothelial COX (cyclooxygenase) evokes potent vasodilation in some blood vessels but is paradoxically responsible for endothelium-dependent constriction (EDC) in others. Prostaglandin I2 production and EDC may be enhanced in diseases such as hypertension. However, how PGIS (prostaglandin I2 synthase) deficiency affects EDC and how this is implicated in the consequent cardiovascular pathologies remain largely unknown. METHODS: Experiments were performed with wild-type, Pgis knockout (Pgis-/-) and Pgis/thromboxane-prostanoid receptor gene (Tp) double knockout (Pgis-/-Tp-/-) mice and Pgis-/- mice transplanted with unfractionated wild-type or Cox-1-/- bone marrow cells, as well as human umbilical arteries. COX-derived prostanoids were measured by high-performance liquid chromatography-mass spectrometry. Vasomotor responses of distinct types of arteries were assessed by isometric force measurement. Parameters of hypertension, vascular remodeling, and cardiac hypertrophy in mice at different ages were monitored. RESULTS: PGF2α, PGE2, and a trace amount of PGD2, but not thromboxane A2 (TxA2), were produced in response to acetylcholine in Pgis-/- or PGIS-inhibited arteries. PGIS deficiency resulted in exacerbation or occurrence of EDC ex vivo and in vivo. Endothelium-dependent hyperpolarization was unchanged, but phosphorylation levels of eNOS (endothelial nitric oxide synthase) at Ser1177 and Thr495 were altered and NO production and the NO-dependent relaxation evoked by acetylcholine were remarkably reduced in Pgis-/- aortas. Pgis-/- mice developed high blood pressure and vascular remodeling at 16 to 17 weeks and subsequently cardiac hypertrophy at 24 to 26 weeks. Meanwhile, blood pressure and cardiac parameters remained normal at 8 to 10 weeks. Additional ablation of TP (TxA2 receptor) not only restrained EDC and the downregulation of NO signaling in Pgis-/- mice but also ameliorated the cardiovascular abnormalities. Stimulation of Pgis-/- vessels with acetylcholine in the presence of platelets led to increased TxA2 generation. COX-1 disruption in bone marrow-derived cells failed to affect the development of high blood pressure and vascular remodeling in Pgis-/- mice though it largely suppressed the increase of plasma TxB2 (TxA2 metabolite) level. CONCLUSIONS: Our study demonstrates that the non-TxA2 prostanoids/TP axis plays an essential role in mediating the augmentation of EDC and cardiovascular disorders when PGIS is deficient, suggesting TP as a promising therapeutic target in diseases associated with PGIS insufficiency.

Inhaled Epoprostenol Compared With Nitric Oxide for Right Ventricular Support After Major Cardiac Surgery.

BACKGROUND: Right ventricular failure (RVF) is a leading driver of morbidity and death after major cardiac surgery for advanced heart failure, including orthotopic heart transplantation and left ventricular assist device implantation. Inhaled pulmonary-selective vasodilators, such as inhaled epoprostenol (iEPO) and nitric oxide (iNO), are essential therapeutics for the prevention and medical management of postoperative RVF. However, there is limited evidence from clinical trials to guide agent selection despite the significant cost considerations of iNO therapy. METHODS: In this double-blind trial, participants were stratified by assigned surgery and key preoperative prognostic features, then randomized to continuously receive either iEPO or iNO beginning at the time of separation from cardiopulmonary bypass with the continuation of treatment into the intensive care unit stay. The primary outcome was the composite RVF rate after both operations, defined after transplantation by the initiation of mechanical circulatory support for isolated RVF, and defined after left ventricular assist device implantation by moderate or severe right heart failure according to criteria from the Interagency Registry for Mechanically Assisted Circulatory Support. An equivalence margin of 15 percentage points was prespecified for between-group RVF risk difference. Secondary postoperative outcomes were assessed for treatment differences and included: mechanical ventilation duration; hospital and intensive care unit length of stay during the index hospitalization; acute kidney injury development including renal replacement therapy initiation; and death at 30 days, 90 days, and 1 year after surgery. RESULTS: Of 231 randomized participants who met eligibility at the time of surgery, 120 received iEPO, and 111 received iNO. Primary outcome occurred in 30 participants (25.0%) in the iEPO group and 25 participants (22.5%) in the iNO group, for a risk difference of 2.5 percentage points (two one-sided test 90% CI, -6.6% to 11.6%) in support of equivalence. There were no significant between-group differences for any of the measured postoperative secondary outcomes. CONCLUSIONS: Among patients undergoing major cardiac surgery for advanced heart failure, inhaled pulmonary-selective vasodilator treatment using iEPO was associated with similar risks for RVF development and development of other postoperative secondary outcomes compared with treatment using iNO. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03081052.

Patterns and Outcomes of Epoprostenol Use in Infants with Congenital Diaphragmatic Hernia Requiring Extracorporeal Life Support.

OBJECTIVE: To describe our experience utilizing epoprostenol for pulmonary hypertension (PH) in infants with congenital diaphragmatic hernia (CDH) requiring extracorporeal life support (ECLS). STUDY DESIGN: We retrospectively reviewed infants diagnosed with CDH who required ECLS at our institution from 2013 to 2023. Data collected included demographics, disease characteristics, medication administration patterns, and hospital outcomes. We first compared infants who received intravenous epoprostenol and those who did not. Among infants who received epoprostenol, we compared survivors and nonsurvivors. χ² test/Fisher's exact and Mann-Whitney tests were used, with significance defined at P < .05. RESULTS: Fifty-seven infants were included; 40 (70.2%) received epoprostenol. Infants receiving epoprostenol had lower observed/expected total fetal lung volume (O/E TFLV) on magnetic resonance imaging (20 vs 26.2%, P = .042) as well as higher prenatal frequency of liver-up (90 vs 64.7%, P = .023) and "severe" classification (67.5 vs 35.3%, P = .007). Survival with and without epoprostenol was comparable (60% vs 64%, P = .23). Of those receiving epoprostenol, both survivors and nonsurvivors had similar prenatal indicators of disease severity. Most (80%) of hernia defects were classified as type C/D and 68% were repaired <72 hours after ECLS cannulation. The median age at initiation of epoprostenol was day of life 6 (IQR: 4, 7) in survivors and 8 (IQR: 7, 16) in nonsurvivors (P = .012). Survivors had shorter ECLS duration (11 vs 20 days, P = .049). Of nonsurvivors, refractory PH was the cause of death for 13 infants (81%). CONCLUSIONS: In infants with CDH requiring ECLS, addition of epoprostenol appears promising and earlier initiation may affect survival.

A Narrative Review on the Administration of Inhaled Prostaglandins in Critically Ill Adult Patients With Acute Respiratory Distress Syndrome.

OBJECTIVE: To describe the effect of inhaled prostaglandins on both oxygenation and mortality in critically ill patients with acute respiratory distress syndrome (ARDS), with a focus on safety and efficacy in coronavirus disease 2019 (COVID-19)-associated ARDS and non-COVID-19 ARDS. DATA SOURCES: A literature search of MEDLINE was performed using the following search terms: inhaled prostaglandins, inhaled epoprostenol, inhaled nitric oxide, ARDS, critically ill. All abstracts were reviewed. STUDY SELECTION AND DATA EXTRACTION: Relevant English-language reports and studies conducted in humans between 1980 and June 2023 were considered. DATA SYNTHESIS: Data regarding inhaled prostaglandins and their effect on oxygenation are limited but show a benefit in patients who respond to therapy, and data pertaining to their effect on mortality is scarce. Concerns exist regarding the formulation of inhaled epoprostenol (iEPO) utilized in addition to modes of medication delivery; however, the limited data surrounding their use have shown a reasonable safety profile. Other avenues and beneficial effects may exist with inhaled prostaglandins, such as use in COVID-19-associated ARDS or non-COVID-19 ARDS patients undergoing noninvasive mechanical ventilation or during patient transport. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: The use of inhaled prostaglandins can be considered in critically ill patients with COVID-19-associated ARDS or non-COVID-19 ARDS who are experiencing difficulties with oxygenation refractory to nonpharmacologic strategies. CONCLUSIONS: The use of iEPO and other inhaled prostaglandins requires further investigation to fully elucidate their effects on clinical outcomes, but it appears these medications may have a potential benefit in COVID-19-associated ARDS and non-COVID-19 ARDS patients with refractory hypoxemia but with little effect on mortality.

A Comparison of the Anticoagulation Efficacy and Safety of Epoprostenol to Heparin and Citrate in Children Receiving Continuous Renal Replacement Therapy.

INTRODUCTION: Anticoagulants are used in continuous renal replacement therapy (CRRT) to prolong filter life. There are no prior investigations directly comparing epoprostenol to more commonly used forms of anticoagulation in children. Therefore, the primary aim of this study was to assess the efficacy and safety of epoprostenol as compared to heparin and citrate anticoagulation in a pediatric cohort. METHODS: We performed a retrospective analysis of all patients <18 years of age admitted to an academic quaternary care children's hospital from 2017-2022 who received epoprostenol, heparin, or citrate exclusively for CRRT anticoagulation. Efficacy was evaluated by comparing the hours to the first unintended filter change and the ratio of filters used to CRRT days. Safety was assessed by evaluating changes in platelet count and vasoactive-ionotropic score (VIS). RESULTS: Of 101 patients, 44 received epoprostenol (43.6%), 38 received heparin (37.6%), and 19 received citrate (18.8%). The first filter change was more commonly planned in patients receiving anticoagulation with epoprostenol (43%) as compared to citrate (11%) or heparin (29%) (p = 0.034). Of those patients where the first filter change was unintended (n = 33), there were greater median hours until the filter was replaced in those receiving epoprostenol (29) when compared to citrate (21) (p = 0.002) or heparin (18) (p = 0.003). There was a smaller median ratio of filters used to days on therapy in the patients that received epoprostenol (0.53) when compared to citrate (1) (p = 0.003) or heparin (0.75) (p = 0.001). For those receiving epoprostenol, there was no significant decrease in platelet count when comparing values prior to CRRT initiation through 7 days of therapy. There was no significant difference in VIS when comparing values prior to CRRT initiation through the first 2 days of CRRT. CONCLUSIONS: Epoprostenol-based anticoagulation is effective when compared to other anticoagulation strategies used in pediatric CRRT with a favorable side effect profile.

Tolerability, safety and survival in patients with severe pulmonary arterial hypertension treated with intravenous epoprostenol (Veletri®): a prospective, 6-months, open label, observational, non-interventional study.

BACKGROUND: Epoprostenol AS (Veletri®), a thermostable epoprostenol formulation, provides better drug stability and improved clinical use compared to previous epoprostenol formulations. This study aims to expand clinical experience in the use of Veletri®, especially regarding tolerability, safety and survival. METHODS: Pulmonary arterial hypertension (PAH) patients at high risk despite pretreatment with at least double oral combination therapy and with clinical indication for epoprostenol (Veletri®) treatment were consecutively included in this prospective, open label, observational, non-interventional study. Clinical data were assessed at baseline, after 3 and 6 months. Adverse events (AEs) and serious adverse events (SAEs) were documented. Survival from initiation of Veletri® was assessed at last patient out. RESULTS: Fifteen patients (60 ± 13.7 years, WHO functional class III (n = 10) or IV (n = 5), severely impaired right ventricular function, mean pulmonary arterial pressure 54.8 ± 8.9 mmHg, mean pulmonary vascular resistance 4.4 ± 0.7 (median 3.8) Wood Units) were enrolled and treated with a mean dosage of 7.9 ± 3.9 (median 7.5) ng/kg/min. Eleven patients completed the study (treatment withdrawal n = 1, death n = 3). After a mean follow-up of 19.1 ± 13.5 (median 18.0) months, seven patients died and three were listed for lung transplantation. Seven AEs (nausea n = 3, diarrhea n = 1, flushing n = 2, headaches n = 1) and three SAEs (catheter infection n = 2, catheter occlusion n = 1) were related to Veletri®. The 1- and 2-year survival rates were 73.3% and 52.4%, respectively. CONCLUSIONS: The study showed that safety and tolerability of epoprostenol AS (Veletri®) was comparable to previous prostacyclin formulations and was feasible for most patients. The maximum tolerable dosage was lower than dosages reported in the literature. In future applications/trials the up-titration process should be pushing for higher dosages of epoprostenol in the occurrence of side effects, as the achievement of a high and effective dosage is crucial for the clinical benefit of the patients. Survival was as expected in these prevalent severely impaired patients. Trial registration The study was registered in the EUPAS registry (EUPAS32492).

Continuous Prostanoid Initiation in Severe Pulmonary Hypertension in the Pediatric Cardiac Intensive Care Unit.

OBJECTIVE: Limited data exists regarding prostanoid (PGI2) use in critically ill patients with pulmonary hypertension. (PH) in the pediatric cardiac intensive care unit (CICU) setting. MATERIALS AND METHODS: Single center, retrospective study of patients with diagnosis of PH who received continuous PGI2 and were admitted to CICU from January/2015 to April/2022. Data collected included patient demographics and clinical characteristics including diagnosis, etiology of PH, vasoactive and ventilatory support, length of stay, and survival. Type, initial, maximum, and final dose of PGI2 as well as hemodynamic data was obtained. Data reported as mean ± standard deviation. Significance taken p value < 0.05. RESULTS: 24 patients received PGI2 therapy at a mean age of 3.1 years, range (0-16.6 years). PGI2 was in the form of IV epoprostenol in 12 patients, IV treprostinil in 6, and SQ treprostinil in 6 patients. Mean initial dose was 2.79 ng/kg/min, max dose 18.75 ng/kg/min, and mean duration of therapy was 38.5 days. At PGI2 initiation, 21 (87.5%) were on vasoactive infusions, 19 (79.2%) mechanically ventilated (MV), and 6 (25%) were on extracorporeal membrane oxygenation (ECMO). The in-hospital mortality rate was 37.5% (n = 9). Patients MV and on ECMO support had higher risk of death (p = 0.04, and < 0.01, respectively). CONCLUSION: PGI2 therapy was tolerated in approximately 50% of patients with the most common side effect being hypotension leading to discontinuation in 1/3rd of patients. Ongoing evaluation of the benefits of PGI2 for patients in the CICU setting will help better identify patient selection, type, and dosing of PGI2.

Risk factors and treatment of oxygenator high-pressure excursions during cardiopulmonary bypass.

INTRODUCTION: A high-pressure excursion (HPE) is a sudden increase in oxygenator inlet pressure during cardiopulmonary bypass (CPB). The aims of this study were to identify factors associated with HPE, to describe a treatment protocol utilizing epoprostenol in severe cases, and to assess early outcome in HPE patients. METHODS: Patients who underwent cardiac surgery with cardiopulmonary bypass at Sahlgrenska University Hospital 2016-2018 were included in a retrospective observational study. Pre- and post-operative data collected from electronic health records, local databases, and registries were compared between HPE and non-HPE patients. Factors associated with HPE were identified with logistic regression models. RESULTS: In total, 2024 patients were analyzed, and 37 (1.8%) developed HPE. Large body surface area (adjusted Odds Ratio (aOR): 1.43 per 0.1 m2; 95% confidence interval (CI): 1.16-1.76, p < 0.001), higher hematocrit during CPB (aOR: 1.20 per 1%; (1.09-1.33), p < 0.001), acute surgery (aOR: 2.98; (1.26-6.62), p = 0.018), and previous stroke (aOR: 2.93; (1.03-7.20), p = 0.027) were independently associated with HPE. HPE was treated with hemodilution (n = 29, 78.4%), and/or extra heparin (n = 23, 62.2%), and/or epoprostenol (n = 12, 32.4%). No oxygenator change-out was necessary. While there was no significant difference in 30-day mortality (2.7% vs 3.2%, p = 1.0), HPE was associated with a higher perioperative stroke rate (8.1% vs 1.8%, aOR 5.09 (1.17-15.57), p = 0.011). CONCLUSIONS: Large body surface area, high hematocrit during CPB, previous stroke and acute surgery were independently associated with HPE. A treatment protocol including epoprostenol appears to be a safe option. Perioperative stroke rate was increased in HPE patients.

Evaluation of Continuous Inhaled Epoprostenol in the Treatment of Acute Respiratory Distress Syndrome, Including Patients With SARS-CoV-2 Infection.

BACKGROUND: Acute respiratory distress syndrome (ARDS) management is primarily supportive. Pulmonary vasodilators, such as inhaled epoprostenol (iEPO), have been shown to improve PaO2:FiO2 (PF) and are used as adjunctive therapy. OBJECTIVE: To identify the positive response rate and variables associated with response to iEPO in adults with ARDS. A positive response to iEPO was defined as a 10% improvement in PF within 6 hours. METHODS: This retrospective study included adults with ARDS treated with iEPO. The primary endpoint was the variables associated with a positive response to iEPO. Secondary endpoints were positive response rate and the change in PF and SpO2:FiO2 within 6 hours. Statistical analysis included multivariable regression. RESULTS: Three hundred thirty-one patients were included. As baseline PF increased, the odds of responding to iEPO decreased (odds ratio [OR], 0.752, 95% CI, 0.69-0.819, p < 0.001). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related ARDS (OR 0.478, 95% CI, 0.281-0.814, p = 0.007) was associated with decreased odds of a positive response to iEPO. The total population had a 68.3% positive response rate to iEPO. SARS-CoV-2-related ARDS and non-SARS-CoV-2-related ARDS had a 59.5% and 72.7% positive response rate, respectively. iEPO significantly improved PF (71 vs 95, P < 0.001) in the whole population. CONCLUSION AND RELEVANCE: iEPO was associated with a positive effect in a majority of moderate-to-severe ARDS patients, including patients with SARS-CoV-2-related ARDS. Lower baseline PF and non-SARS-CoV-2-related ARDS were significantly associated with a positive response to iEPO. The ability to predict which patients will respond to iEPO can facilitate better utilization.

Evaluation of Inhaled Alprostadil in Hospitalized Adult Patients.

BACKGROUND: Intermittent inhaled alprostadil (iPGE1) may be a viable alternative to inhaled nitric oxide or epoprostenol for management of right ventricular failure, pulmonary hypertension (pHTN) or acute respiratory distress syndrome (ARDS). However, limited evidence exists regarding iPGE1 use in adults, ideal dosing strategies, or optimal use cases. OBJECTIVE: To describe the clinical characteristics of patients receiving iPGE1 and identify specific sub-populations warranting further research. METHODS: This was a single-center, retrospective, descriptive analysis of inpatients who received at least one dose of iPGE1. The primary outcome was to describe patient characteristics and alprostadil dosing strategies. Secondary outcomes included changes in respiratory support requirements, hemodynamics, and inotropic/vasoactive use. Outcomes were stratified and compared based on primary therapeutic indication (cardiac or pulmonary). RESULTS: Fifty-four patients received iPGE1 40 (75%) for pulmonary (pHTN or ARDS) and 14 (25%) for cardiac indications. There was no difference between indications in the number of patients de-escalated from level of respiratory (53% vs 57%, P = 0.76), inotropic (70% vs 57%, P = 0.39), or vasopressor support (78% vs 57%, P = 0.17). Furthermore, there was no significant improvement in cardiopulmonary parameters at multiple time intervals after iPGE1 initiation. CONCLUSION AND RELEVANCE: This is the largest study to date on the use of intermittent iPGE1 in adults. Alprostadil was safely utilized in novel populations; however, efficacy as evaluated by clinical or surrogate endpoints could not be demonstrated and further investigation is needed to determine its potential and optimal place in therapy.

A retrospective review of implementation of an inhaled epoprostenol protocol in the emergency department.

INTRODUCTION: Inhaled epoprostenol is a selective pulmonary vasodilator that has shown a potentially broad number of applications in the management of critically ill patients. To date, the vast majority of the literature with regard to efficacy, indications for use, and adverse effects of inhaled epoprostenol is focused on use of this agent in critical care settings, with relatively little literature describing use of inhaled epoprostenol in the Emergency Department. This retrospective review sought to examine instances in which inhaled epoprostenol was administered in the Emergency Department of a tertiary-care, Level I trauma center following implementation of a clinical pathway for administration of this medication for cases of refractory hypoxemia, RV dysfunction, and refractory hypoxemia. Primary outcomes were monitoring for adverse effects (i.e. hypotension), trend in FiO2 requirement over time, and clinical indication for initiation of inhaled epoprostenol. METHODS: An automated review was performed to query cases in which inhaled epoprostenol had been initiated in the Emergency Department following adoption of the inhaled epoprostenol clinical pathway. Cases were excluded if the medication was initiated in the prehospital setting, ordered but not administered, or administered for a period of <1 h. Vital signs and co-administration of vasopressors were followed before and following epoprostenol administration to assess for change over time. Clinical indication of epoprostenol administration was assessed via manual chart review. RESULTS: Inhaled epoprostenol was administered in 20 instances, with 15 cases ultimately meeting inclusion criteria. There were no cases of clinically significant hypotension (MAP <65) in any of the cases in which inhaled epoprostenol was administered in the Emergency Department, and mean vasopressor requirement did not increase over time. A majority of patients saw a reduction in FiO2 requirement following administration of inhaled epoprostenol. The most common indication for initiation of inhaled epoprostenol based on manual chart review was pulmonary embolism. DISCUSSION: In this review of cases in which inhaled epoprostenol was administered following adoption of a clinical pathway for medication administration, there were no cases of hypotension or other adverse effects that appear to be attributable to medication administration. Pulmonary embolism and refractory hypoxemia were the most common noted indications for administration of inhaled epoprostenol. Further research is warranted regarding development of clinical protocols for administration of inhaled pulmonary vasodilators in the Emergency Department setting.

Inhaled Pulmonary Vasodilator Utilization and Cost Following Initiation of a Protocol in a Quaternary Academic Heart Center Intensive Care Unit.

OBJECTIVES: To examine the use of inhaled nitric oxide (iNO) and inhaled epoprostenol (iPGI2) before and after implementation of an iPGI2-preferential protocol and the associated cost differences after rollout. DESIGN: A single-center, retrospective analysis. SETTING: A quaternary university hospital. PARTICIPANTS: All patients admitted to the Heart Center Intensive Care Unit (HCICU) who required inhaled pulmonary vasodilator use between December 2017 and November 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The HCICU comprised 84% of hospital-wide iNO utilization and 59% of hospital-wide iPGI2 use across the entire study period. There was no significant difference in postsurgical HCICU admission rates across the study period. There was a significant decrease in iNO mean monthly use from 578 ± 230 to 69 ± 71 hours, and a significant concurrent increase in iPGI2 from 756 ± 443 to 1,210 ± 547 hours after the implementation of a protocol. There were no changes in the average length of ICU stay between the 2 time periods. The protocol implementation led to a projected annual savings of roughly $1,180,000. CONCLUSIONS: These findings showed that multidisciplinary protocol development and implementation can have a substantial impact on medication utilization and lead to significant reductions in cost.

In-vitro and in-vivo comparisons of high versus low concentrations of inhaled epoprostenol to adult intubated patients.

BACKGROUND: Inhaled epoprostenol (iEPO) has been shown to reduce pulmonary artery pressure and improve oxygenation. iEPO is mainly delivered via a syringe pump with feed tubing connected to a vibrating mesh nebulizer with high or low formulation concentration delivery. METHODS: An in vitro study and a two-period retrospective case-control study were implemented. The in vitro study compared iEPO delivery via invasive ventilation at low concentrations of 7.5, and 15 mcg/mL and high concentration at 30 mcg/mL, to deliver the ordered dose of 30 and 50 ng/kg/min for three clinical scenarios with predicted body weight of 50, 70 and 90 kg. While in the clinical study, adult patients receiving iEPO via invasive ventilation to treat refractory hypoxemia, pulmonary hypertension, or right ventricular failure were included. 80 patients received low concentration iEPO at multiple concentrations (2.5, 7.5, and 15 mcg/mL, depending on the ordered dose) from 2015 to 2017, while 84 patients received high concentration iEPO at 30 mcg/mL from 2018 to 2019. RESULTS: In the in vitro study, there were no significant differences in aerosol deposition between high vs low concentrations of iEPO at a dose of 50 ng/kg/min. In the clinical study, age, gender, ethnicity, and indications for iEPO were similar between high and low concentration groups. After 30-120 min of iEPO administration, both delivery strategies significantly improved oxygenation in hypoxemic patients and reduced mean pulmonary arterial pressure (mPAP) for patients with pulmonary hypertension. However, no significant differences of the incremental changes were found between two delivery groups. Compared to low concentration, high concentration delivery group had better adherence to the iEPO weaning protocol (96% vs 71%, p < 0.001), fewer iEPO syringes utilized per patient (5 [3, 10] vs 12 [6, 22], p = 0.001), and shorter duration of invasive ventilation (6 [3, 12] vs 9 [5, 18] days, p = 0.028). Intensive care unit length of stay and mortality were similar between two groups. CONCLUSION: Compared to low concentration delivery of iEPO, high concentration iEPO via a vibrating mesh nebulizer maintained clinical benefits and increased clinician compliance with an iEPO weaning protocol, required less medication preparation time, and shortened duration of invasive ventilation.

Responsiveness of Inhaled Epoprostenol in Respiratory Failure due to COVID-19.

BACKGROUND: Inhaled pulmonary vasodilators are used as adjunctive therapies for the treatment of refractory hypoxemia. Available evidence suggest they improve oxygenation in a subset of patients without changing long-term trajectory. Given the differences in respiratory failure due to COVID-19 and "traditional" ARDS, we sought to identify their physiologic impact. METHODS: This is a retrospective observational study of patients mechanically ventilated for COVID-19, from the ICUs of 2 tertiary care centers, who received inhaled epoprostenol (iEpo) for the management of hypoxemia. The primary outcome is change in PaO2/FiO2. Additionally, we measured several patient level features to predict iEpo responsiveness (or lack thereof). RESULTS: Eighty patients with laboratory confirmed SARS-CoV2 received iEpo while mechanically ventilated and had PaO2/FiO2 measured before and after. The median PaO2/FiO2 prior to receiving iEpo was 92 mmHg and interquartile range (74 - 122). The median change in PaO2/FiO2 was 9 mmHg (-9 - 37) corresponding to a 10% improvement (-8 - 41). Fifty-percent (40 / 80) met our a priori definition of a clinically significant improvement in PaO2/FiO2 (increase in 10% from the baseline value). Prone position and lower PaO2/FiO2 when iEpo was started predicted a more robust response, which held after multivariate adjustment. For proned individuals, improvement in PaO2/FiO2 was 14 mmHg (-6 to 45) vs. 3 mmHg (-11 - 20), p = 0.04 for supine individuals; for those with severe ARDS (PaO2/FiO2 < 100, n = 49) the median improvement was 16 mmHg (-2 - 46). CONCLUSION: Fifty percent of patients have a clinically significant improvement in PaO2/FiO2 after the initiation of iEpo. This suggests it is worth trying as a rescue therapy; although generally the benefit was modest with a wide variability. Those who were prone and had lower PaO2/FiO2 were more likely to respond.

Changes in Oxygen Saturation and Mean Arterial Pressure With Inhaled Epoprostenol in Transport.

OBJECTIVE: Patients with hypoxemic respiratory failure have traditionally been considered one of the riskiest patient populations to transport, given the potential for desaturation with movement. We performed a retrospective cohort study to analyze our experience using inhaled epoprostenol in transport, with a primary objective of assessing change in the oxygen saturation throughout the transport. METHODS: The transport records of patients with severe hypoxemic respiratory failure or right heart failure, transported on inhaled epoprostenol, were reviewed. The primary outcome was the change in SpO2 from the start of the inhaled epoprostenol transport to the time of handover of care at the receiving institution. The secondary outcome was the change in the mean arterial pressure (MAP). RESULTS: Comparing the initial SpO2 to the final, there was no significant difference in oxygenation between time 0 and the transfer of care at the receiving hospital at 91% versus 93% (interquartile range [IQR] 86.0-93.5 vs 87.5-96.0, P = .49). Comparing the SpO2 for those who had inhaled epoprostenol started by the transport team showed a larger change at 86% compared to 93% (IQR: 83.0-91.0 vs 86.5-94.5, P = .04). There was no change in the median MAP from time 0 to the end of the transport (77 vs 75 mm Hg, IQR, 67.5-84.8 vs 68.5-85.8, P = .70). CONCLUSIONS: In this study, patients with severe cardiopulmonary compromise transported on inhaled epoprostenol had no significant change in their median oxygen saturations, with the overall population increasing from 91% to 93%. When inhaled epoprostenol was initiated by the transport team, the improvement was clinically and statistically significant with an increase in SpO2 from 86% to 93%, with a final oxygen saturation comparable to those who were on the medication at the time of the team's arrival.

Comparison of Fixed-Dose Inhaled Epoprostenol and Inhaled Nitric Oxide for Acute Respiratory Distress Syndrome in Critically Ill Adults.

PURPOSE: Several reports have demonstrated similar effects on oxygenation between inhaled epoprostenol (iEPO) compared to inhaled nitric oxide (iNO) for acute respiratory distress syndrome (ARDS). Previous studies directly comparing oxygenation and clinical outcomes between iEPO and iNO exclusively in an adult ARDS patient population utilized a weight-based dosing strategy. The purpose of this study was to compare the clinical and economic impact between iNO and fixed-dosed iEPO for ARDS in adult intensive care unit (ICU) patients. METHODS: This retrospective cohort study was conducted at a major academic medical center between January 1, 2014, and October 31, 2018. Patients ≥18 years of age with moderate-to-severe ARDS were included. The primary end point was to compare the mean change in partial arterial oxygen pressure to fraction of inspired oxygen (Pao 2: Fio 2) at 4 hours from baseline between iEPO and iNO. Other secondary aims were total acquisition drug costs, in-hospital mortality, ICU and hospital length of stay, and duration of mechanical ventilation. RESULTS: A total of 239 patients were included with 139 (58.2%) and 100 (41.8%) in the iEPO and iNO groups, respectively. The mean change in Pao 2: Fio 2 at 4 hours from baseline in the iEPO and iNO groups were 31.4 ± 54.6 and 32.4 ± 42.7 mm Hg, respectively (P = .88). The responder rate at 4 hours was similar between iEPO and iNO groups (64.7% and 66.0%, respectively, P = .84). Clinical outcomes including mortality, overall hospital and ICU length of stay, and mechanical ventilation duration were similar between iEPO and iNO groups. Estimated annual cost-savings realized with iEPO was USD1 074 433. CONCLUSION: Fixed-dose iEPO was comparable to iNO in patients with moderate-to-severe ARDS for oxygenation and ventilation parameters as well as clinical outcomes. Significant cost-savings were realized with iEPO use.

Prognostic Value of Change in Cardiac Index After Prostacyclin Initiation in Pediatric Pulmonary Hypertension.

Invasive hemodynamic assessment remains the gold standard for the diagnosis of pediatric pulmonary hypertension and for longitudinal assessment of response to therapy. This analysis sought to describe the changes in hemodynamic variables after initiation of prostacyclin therapy and determine which changes bear predictive power of adverse clinical outcomes. A retrospective chart review of established patients at Cincinnati Children's Hospital with pulmonary arterial hypertension (PAH) who required prostacyclin therapy between 2004 and 2018 was performed. The baseline hemodynamic parameters at diagnosis as well as change in those parameters between initial catheterization and post-prostacyclin initiation catheterization were independent variables. Cox proportional hazard regression and recursive partitioning analysis were used to characterize which hemodynamic factors predicted the composite adverse outcome (CAO) defined as death, lung transplantation, or reverse Pott's shunt surgery. During the study period, 29 patients met inclusion criteria in which there were 7 CAOs: 4 deaths, 3 lung transplants, and 2 reverse Pott's shunts. Median time between catheterizations was 86 days and between the initiation of prostacyclin therapy and the second catheterization was 54 days. Cox regression revealed that only baseline pulmonary artery pressure (> 51 mmHg) and a failure to increase cardiac index illustrated statistically significant hazard for occurrence of the CAO (p < 0.01). These criteria significantly dichotomized the population in a Kaplan-Meier analysis into likelihoods of experiencing the CAO. While controlling for other hemodynamic variables, the absence of augmentation of cardiac index after the initiation of prostacyclin therapy is a valuable prognostic indicator of adverse PAH outcomes in pediatrics.

Droplet Size and Distribution of Nebulized 3% Sodium Chloride, Albuterol, and Epoprostenol by Phase Doppler Particle Analyzer.

BACKGROUND: Aerosolized drug therapy administered to mechanically ventilated patients is a standard part of pulmonary critical care medicine. Aerosol particle size and distribution are important factors in the optimal delivery of aerosolized drugs to ventilated patients. OBJECTIVE: The objective of this study was to characterize aerosol droplet size and distribution with laser diffraction for nebulized 3% sodium chloride, albuterol, and epoprostenol sodium (containing glycine) delivered via Aeroneb Solo Mesh Nebulizers (Aerogen, Mountain View, California). METHODS: A series of functional flow tests were run on each of 8 Solo mesh nebulizers before the study to verify accuracy of flow rates in milliliters per minute. Aerosolized droplets exiting the nebulizer heads were then measured using a phase Doppler particle analyzer. Data collected during delivery of 3% sodium chloride, albuterol, and epoprostenol sodium included aerosol droplet size distribution, mass median aerodynamic diameter (MMAD), and geometric standard deviation. For each Solo nebulizer, droplet size measurements were taken 2 cm away from the nebulizer head and 2 cm away from the wye of a heated, humidified adult ventilator circuit. For measurements taken at the wye, 4 distinct, continuous flow rates (2, 10, 20, and 40 L/min) were generated by an air pump to simulate inspiratory flows delivered with mechanical ventilation. The expiratory limb was capped, and the nebulizer head was inserted into the breathing circuit upstream of the humidifier. RESULTS: Each Solo nebulizer met Aerogen's recommended minimum flow rate of 0.2 mL/min, ranging from 0.23 to 0.31 mL/min. The MMAD of the 3 tested aerosols was several times smaller when measured at the wye outlet of the heated/humidified breathing circuit (0.82-2.73 µm) compared with droplets measured directly at the nebulizer outlet (MMAD, 4.6-7.3 µm). There was also significant variability across Solo heads with some ventilator flow rates. The mean MMAD at the wye for the 3% sodium chloride solution, albuterol, and epoprostenol test solutions was 1.62 µm, 1.09 µm, and 1.18 µm, respectively. The mean MMAD at the nebulizer for the 3% sodium chloride solution, albuterol, and epoprostenol test solutions was 5.37 µm, 5.73 µm, and 6.73 µm, respectively. CONCLUSIONS: Results from this study suggest that particle size of aerosolized drugs administered via a commonly used setup for delivery of in-line aerosols to mechanically ventilated patients may be several times smaller than expected and may result in less drug being delivered to the patient than previously realized.(Curr Ther Res Clin Exp. 2021; 82:XXX-XXX)© 2021 Elsevier HS Journals, Inc.

Development of a severe mesenteric traction syndrome during major abdominal surgery is associated with increased postoperative morbidity: Secondary data analysis on prospective cohorts.

PURPOSE: MTS is elicited during open abdominal surgery and is characterized by facial flushing, hypotension, and tachycardia in response to the release of prostacyclin (PGI2) to plasma. MTS seems to affect postoperative morbidity, but data from larger cohorts are lacking. We aimed to determine the impact of severe mesenteric traction syndrome (MTS) on postoperative morbidity in patients undergoing open upper gastrointestinal surgery. METHODS: The study was a secondary analysis of data from three cohorts (n = 137). The patients were graded for severity of MTS intraoperatively, and hemodynamic variables and blood samples for plasma 6-keto-PGF1α, a stable metabolite of PGI2, were obtained at defined time points. Postoperative morbidity was evaluated by the comprehensive complication index (CCI) and the Dindo-Clavien classification (DC). RESULTS: Patients undergoing either esophagectomy (n = 70), gastrectomy (n = 22), liver- (n = 23), or pancreatic resection (n = 22) were included. Severe MTS was significantly associated with increased postoperative morbidity, i.e., CCI ≥ 26.2 (OR 3.06 [95% CI 1.1-6.6]; p = 0.03) and risk of severe complications, i.e., DC ≥3b (OR 3.1 [95% CI 1.2-8.2]; p = 0.023). Furthermore, patients with severe MTS had increased length of stay (OR 10.1 [95% CI 1.9-54.3]; p = 0.007) and were more likely to be admitted to the intensive care unit (OR = 7.3 [95% CI 1.3-41.9]; p = 0.027), but there was no difference in 1-year mortality. CONCLUSION: Occurrence of severe MTS during upper gastrointestinal surgery is associated with increased postoperative morbidity as indicated by an increased rate of severe complications, length of stay, and admission to the ICU. It remains to be determined whether inhibition of MTS enhances postoperative recovery.

Effectiveness of epoprostenol in the management of pulmonary arterial hypertension: findings of an Australian retrospective chart review.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressively fatal disease. Parenteral prostanoids, including intravenous (IV) epoprostenol, are the most effective therapies for PAH. As epoprostenol requires continuous infusion, therapy is challenging and use is managed by specialist units. AIMS: To describe the clinical outcomes for the use of IV epoprostenol in an Australian pulmonary vascular disease unit and identify opportunities to improve its use. METHOD: We conducted a retrospective chart review of all adult patients who received IV epoprostenol for PAH at Prince Charles Hospital. Data were collected at baseline, initiation of epoprostenol and quarterly to the end of the audit period or the discontinuation of epoprostenol. Descriptive statistics were performed and comparisons made to epoprostenol initiation. Kaplan-Meier curves were used to estimate survival outcomes. RESULTS: Thirty-nine patients received epoprostenol therapy. Most (87.2%) were female, had connective tissue disease (46.2%) or idiopathic PAH (35.9%) and had a World Health Organization functional Class of III or IV at initiation. The mean duration of epoprostenol therapy was 2.9 years. Intravenous epoprostenol was associated with favourable outcomes; 1, 3 and 5-year survival rates since initiation of 90.0, 75.8 and 68.2%; robust improvements in functional class; and improvements in 6-min walking distance of 160.4 m at 3 years; 94.9% patients experienced at least one drug-related adverse event and line complications were common. CONCLUSION: Epoprostenol therapy was associated with impressive survival rates and durable improvements in functional outcomes. Epoprostenol therapy is challenging; however, it is manageable by the majority of patients with most experiencing positive, sustainable outcomes.